TNF signaling

Introduction to TNF Signaling

Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine that impacts all cells. It influences cellular responses, including proliferation, differentiation, and death. Owing to its prominent contribution to inflammatory responses, it has been described as a master pro-inflammatory cytokine (1, 2).

TNF is expressed primarily in immune cells, including monocytes and macrophages. It is produced in small amounts by lymphocytes, mast cells, natural killer cells, neutrophils, fibroblasts, endothelial cells, smooth muscle cells, and osteoclasts (3).

TNF signaling is essential in immune system development and functioning, tissue homeostasis, and embryonic development. It also plays a role in pathological events associated with cancer, viral replication, autoimmune diseases, chronic inflammatory diseases, and more (3).

Mechanisms of TNF Signaling and Specific Pathways

The TNF superfamily comprises 19 ligands that signal cellular responses by binding to 29 receptors (1). TNF ligands include TNF-α, TNF-β, LT-β, CD27L, CD30L, CD40L, TRAIL, LIGHT RANKL, TWEAK, APRIL, BAFF, VEGI, and GITRL (4).

The TNF receptor superfamily members can be classified into three groups based on the specific intracellular signal they induce: death domain (DD)- containing receptors, decoy receptors, and TNF receptor-associated factor (TRAF)- binding receptors.

The interactions between TNF superfamily ligands and receptors regulate signaling involved in cell survival, growth, differentiation, and other effector functions of immune and non-immune cells (1).

TNF also activates and regulates signaling pathways, including nuclear factor-κB (NF-κB), JUN N-terminal kinase, p38 mitogen-activated protein kinase, and ERK1/ERK2 to carry out its many roles in cellular function (5).

TWEAK signaling

TWEAK (TNFSF12) is a pro-inflammatory and pro-angiogenic cytokine produced by monocytes, macrophages, dendritic cells, and natural killer cells. Its receptor is Fn14 (TNFRSF12A), expressed on epithelial, endothelial, and nonimmune cells (4).

TWEAK signaling contributes to acute inflammation in tissue repair following injury or disease. It enables the immune system to activate epithelial, endothelial, and stromal cells, initiating tissue repair responses.

Additionally, TWEAK signaling triggers the activation of NF-κB and MAPK pathways to induce inflammation, cell survival, proliferation, migration, and death (1).

Aberrant TWEAK signaling can lead to chronic inflammation, pathological hyperplasia, tissue damage, fibrosis, cancer, and more. Studies have shown that TWEAK signaling is dysregulated in autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel diseases. For instance, TWEAK and its receptor are elevated in patients with SLE and RA. Similarly, TWEAK signaling inhibitors have been shown to reduce the severity of experimental autoimmune encephalomyelitis and chicken infectious anemia (4).

Studies have also observed upregulated TWEAK signaling in cancer, promoting pathological events like tumor cell proliferation, invasion, and migration. TWEAK signaling is a promising target for cancer treatment, and agents targeting TWEAK are currently in preclinical and clinical trials (6).

TNFR1 Signaling

TNFR1 is classified as a death receptor because it has a death domain in its cytoplasmic region. When activated by binding to mTNFα or sTNFα TNFR1 signaling is transmitted into the cell through its death domain. TNFR1 is expressed in all cells (7).

TNFR1 signaling contributes to and exacerbates inflammation by activating NF-κB and MAPK signaling pathways, which in turn upregulates proinflammatory cytokines, chemokines, and other mediators. TNFR1 activation also leads to inflammation by inducing cell death. For example, cell death through apoptosis, pyroptosis, and necroptosis leads to damage-associated molecular patterns (DAMPs) release. These DAMPs activate proinflammatory gene expression in neighboring cells.

Dysregulated TNFR1 signaling is responsible for chronic inflammation associated with autoimmunity, degenerative disorders, and allergies. Growing evidence suggests that TNFR1 may be targeted in treating many immune-related disorders (8). Similarly, anti-TNF agents have successfully treated many inflammatory disorders (9).

TNFR2 Signaling

Unlike TNFR1, TNFR2 does not have a death domain. Thus, it belongs to the non-death receptor group of TNFRSF. TNFR2 signaling is activated when mTNFα binds to it. Its activation promotes cell survival and proliferation, immune system regulation, and tissue regeneration (7). It also suppresses inflammation by downregulating NFκB (10).

TNFR2 is produced by immune, neuronal, and endothelial cells. This localized expression makes it a better therapy option, as agents targeting this pathway may cause fewer side effects (11).

TNFR2 signaling is a crucial player in cancer development and progression. It is highly expressed in many cancers and other cells in the tumor microenvironment (TME), while it is rarely found in normal tissue (10). It contributes to pathological events associated with cancer, including cancer cell proliferation, angiogenesis, invasion and migration, and chemotherapy drug resistance.

Aberrant TNFR2 signaling is associated with poor survival outcomes in Hodgkin’s lymphoma, multiple myeloma, colorectal cancer, non-small cell lung cancer, and ovarian cancer. Increased TNFR2 expression is associated with tumor size and clinical stage in breast cancer.

Due to its significant role in cancer development and progression, TNFR2 is a strong anti-cancer therapy candidate. More research on the role of TNFR2 signaling in the tumor microenvironment is necessary, and targeting TNFR2 represents a promising new approach for cancer therapy (10).

APRIL Mediated Signaling

APRIL (TNFSF13) is a TNF ligand primarily expressed in myeloid cells. It signals by binding to receptors BAFF-R (TNFRSF13C), BCMA (TNFRSF13A/17), and TACI (TNFRSF13B). Its signaling is involved in B-cell maturation, and survival (1).

Aberrant APRIL-mediated signaling is implicated in cancers, including hematological and lymphoid cancers, infectious diseases like hepatitis C, human immunodeficiency virus (HIV), and malaria infection, and immune-related diseases like systemic lupus erythematosus, chronic variable immunodeficiency (CVID), and allergic asthma (11).

For instance, dysregulated APRIL signaling contributes to multiple myeloma progression and immunosuppression associated with the disease. Increased BAFF levels have been found in oral cavity cancers, breast cancer, and chronic lymphocytic leukemia (CLL)-like disease (11).

TNF signaling is significantly involved in disease processes associated with cancer, diseases of the immune system, inflammatory diseases, and more, making it a therapeutic target for many of these diseases. Medications that target TNF have been successful in treating chronic inflammatory and autoimmune diseases (9). For example, the U.S. Food and Drug Administration (FDA) has approved up to five TNF-targeting drugs, including Etanercept, Infliximab, Adalimumab, Golimumab, and Certolizumab for treating rheumatoid arthritis (RA) (4).

References

1. Dostert C, Grusdat M, Letellier E, Brenner D. The TNF Family of Ligands and Receptors: Communication Modules in the Immune System and Beyond. Physiol Rev. 2019;99(1):115-160.
2. Wajant H, Siegmund D. TNFR1 and TNFR2 in the Control of the Life and Death Balance of Macrophages. Front Cell Dev Biol. 2019;7:91. Published 2019 May 29.
3. Holbrook J, Lara-Reyna S, Jarosz-Griffiths H, McDermott M. Tumour necrosis factor signalling in health and disease. F1000Res. 2019;8:F1000 Faculty Rev-111. Published 2019 Jan 28.
4. Sonar S, Lal G. Role of Tumor Necrosis Factor Superfamily in Neuroinflammation and Autoimmunity. Front Immunol. 2015;6:364.
5. Sabio G, Davis RJ. TNF and MAP kinase signalling pathways. Semin Immunol. 2014;26(3):237-245.
6. Hu G, Zeng W, Xia Y. TWEAK/Fn14 signaling in tumors. Tumour Biol. 2017;39(6):1010428317714624.
7. Gough P, Myles IA. Tumor Necrosis Factor Receptors: Pleiotropic Signaling Complexes and Their Differential Effects. Front Immunol. 2020;11:585880. Published 2020 Nov 25.
8. Li Y, Klein C, Kotlarz D. Dysregulation of Cell Death in Human Chronic Inflammation. Cold Spring Harb Perspect Biol. 2020;12(7):a037036. Published 2020 Jul 1.
9. van Loo G, Bertrand MJM. Death by TNF: a road to inflammation. Nat Rev Immunol. 2023;23(5):289-303.
10. Takahashi H, Yoshimatsu G, Faustman DL. The Roles of TNFR2 Signaling in Cancer Cells and the Tumor Microenvironment and the Potency of TNFR2 Targeted Therapy. Cells. 2022;11(12):1952. Published 2022 Jun 17.
11. Tai YT, Lin L, Xing L, et al. APRIL signaling via TACI mediates immunosuppression by T regulatory cells in multiple myeloma: therapeutic implications. Leukemia. 2019;33(2):426-438.